Publications by authors named "Limas Kupcinskas"

137 Publications

Room for Improvement in the Treatment of Helicobacter pylori Infection: Lessons from the European Registry on H. pylori Management (Hp-EuReg).

J Clin Gastroenterol 2021 Jan 5;Publish Ahead of Print. Epub 2021 Jan 5.

Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) Digestive Service, HM Sanchinarro, Madrid Digestive Unit, Agencia Sanitaria Costa del Sol, Marbella, Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Málaga Digestive Unit, Hospital de Valme, Sevilla Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). Universidad del País Vasco (UPV/EHU), Donostia Hospital de Tomelloso, Ciudad Real, Tomelloso Gastroenterology Unit, Hospital Universitario Central de Asturias, Oviedo Hospital General Universitario de Valencia, Valencia Hospital San Pedro de Alcántara, Cáceres Hospital Río Hortega Hospital Clínico Universitario, Valladolid, Spain Department of Surgical and Clinical Sciences, University of Bologna, Bologna Gastronterology Area, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy Gastroenterology Unit, AM DC Rogaska, Rogaska Slatina DC Bled Slovenj Gradec General Hospital, Slovenj Gradec, Slovenia Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania Department of Pancreatobiliary and Upper GI Diseases, Moscow Clinical Scientific Center, and A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow Gastrocentre Perm, Perm Kazan State Medical University, Kazan, Russia Laboratoire de Bactériologie, Hôpital Pellegrin, Bordeaux Cedex, France Trinity College Dublin, Faculty of Health Sciences, Trinity College Dublin, Dublin/IE, Faculty of Health Sciences, Dublin, Ireland.

Background: Managing Helicobacter pylori infection requires constant decision making, and each decision is open to possible errors.

Aim: The aim was to evaluate common mistakes in the eradication of H. pylori, based on the "European Registry on Helicobacter pylori management".

Methods: European Registry on Helicobacter pylori management is an international multicentre prospective noninterventional registry evaluating the decisions and outcomes of H. pylori management by European gastroenterologists in routine clinical practice.

Results: Countries recruiting more than 1000 patients were included (26,340 patients). The most common mistakes (percentages) were: (1) To use the standard triple therapy where it is ineffective (46%). (2) To prescribe eradication therapy for only 7 to 10 days (69%). (3) To use a low dose of proton pump inhibitors (48%). (4) In patients allergic to penicillin, to prescribe always a triple therapy with clarithromycin and metronidazole (38%). (5) To repeat certain antibiotics after eradication failure (>15%). (6) Failing to consider the importance of compliance with treatment (2%). (7) Not to check the eradication success (6%). Time-trend analyses showed progressive greater compliance with current clinical guidelines.

Conclusion: The management of H. pylori infection by some European gastroenterologists is heterogeneous, frequently suboptimal and discrepant with current recommendations. Clinical practice is constantly adapting to updated recommendations, although this shift is delayed and slow.
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http://dx.doi.org/10.1097/MCG.0000000000001482DOI Listing
January 2021

Endogenous motion of liver correlates to the severity of portal hypertension.

World J Gastroenterol 2020 Oct;26(38):5836-5848

Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania.

Background: Degree of portal hypertension (PH) is the most important prognostic factor for the decompensation of liver cirrhosis and death, therefore adequate care for patients with liver cirrhosis requires timely detection and evaluation of the presence of clinically significant PH (CSPH) and severe PH (SPH). As the most accurate method for the assessment of PH is an invasive direct measurement of hepatic venous pressure gradient (HVPG), the search for non-invasive methods to diagnose these conditions is actively ongoing.

Aim: To evaluate the feasibility of parameters of endogenously induced displacements and strain of liver to assess degree of PH.

Methods: Of 36 patients with liver cirrhosis and measured HVPG were included in the case-control study. Endogenous motion of the liver was characterized by derived parameters of region average tissue displacement signal (, , ) and results of endogenous tissue strain imaging using specific radiofrequency signal processing algorithm. Average endogenous strain and standard deviation of strain were assessed in the regions of interest (ROI) (1 cm × 1 cm and 2 cm × 2 cm in size) and different frequency subbands of endogenous motion (0-10 Hz and 10-20 Hz).

Results: Four parameters showed statistically significant ( < 0.05) correlation with HVPG measurement. The strongest correlation was obtained for the standard deviation of strain (estimated at 0-10 Hz and 2 cm × 2 cm ROI size). Three parameters showed statistically significant differences between patient groups with CSPH, but only showed significant results in SPH analysis. According to ROC analysis area under the curve (AUC) of the parameter reached 0.71 ( = 0.036) for the diagnosis of CSPH; with a cut-off value of 1.28 μm/cm providing 73% sensitivity and 70% specificity. AUC for the diagnosis of CSPH for was 0.78 ( = 0.0024); with a cut-off value of 3.92 μm/cm providing 73% sensitivity and 80% specificity. parameter had an AUC of 0.86 ( = 0.0001) for the diagnosis of CSPH and 0.84 ( = 0.0001) for the diagnosis of SPH. A cut-off value of -132.34 μm yielded 100% sensitivity for both conditions, whereas specificity was 80% and 72% for CSPH and SPH respectively.

Conclusion: The parameters of endogenously induced displacements and strain of the liver correlated with HVPG and might be used for non-invasive diagnosis of PH.
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http://dx.doi.org/10.3748/wjg.v26.i38.5836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579755PMC
October 2020

European Registry on management (Hp-EuReg): patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients.

Gut 2021 01 21;70(1):40-54. Epub 2020 Sep 21.

Clinical Medicine, Zealand University Hospital, Copenhagen University, Copenhagen, Denmark.

Objective: The best approach for management remains unclear. An audit process is essential to ensure clinical practice is aligned with best standards of care.

Design: International multicentre prospective non-interventional registry starting in 2013 aimed to evaluate the decisions and outcomes in management by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables included demographics, previous eradication attempts, prescribed treatment, adverse events and outcomes. Data monitoring was performed to ensure data quality. Time-trend and geographical analyses were performed.

Results: 30 394 patients from 27 European countries were evaluated and 21 533 (78%) first-line empirical treatments were included for analysis. Pretreatment resistance rates were 23% to clarithromycin, 32% to metronidazole and 13% to both. Triple therapy with amoxicillin and clarithromycin was most commonly prescribed (39%), achieving 81.5% modified intention-to-treat eradication rate. Over 90% eradication was obtained only with 10-day bismuth quadruple or 14-day concomitant treatments. Longer treatment duration, higher acid inhibition and compliance were associated with higher eradication rates. Time-trend analysis showed a region-dependent shift in prescriptions including abandoning triple therapies, using higher acid-inhibition and longer treatments, which was associated with an overall effectiveness increase (84%-90%).

Conclusion: Management of infection by European gastroenterologists is heterogeneous, suboptimal and discrepant with current recommendations. Only quadruple therapies lasting at least 10 days are able to achieve over 90% eradication rates. European recommendations are being slowly and heterogeneously incorporated into routine clinical practice, which was associated with a corresponding increase in effectiveness.
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http://dx.doi.org/10.1136/gutjnl-2020-321372DOI Listing
January 2021

A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA.

J Hepatol 2021 Feb 17;74(2):321-329. Epub 2020 Sep 17.

Service d'Hépatologie, Centre national de référence des maladies inflammatoires du foie et des voies biliaires, Hôpital Saint-Antoine, Paris, France.

Background & Aims: In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment.

Methods: We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5× upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12-16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury.

Results: Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n = 43), the primary histologic endpoint was not met (p >0.05). The proportion of patients with ALP <1.67×ULN, a ≥15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p <0.05, each). In contrast to placebo, budesonide reduced mean ALP and 35% of budesonide-treated patients achieved normalisation of ALP (placebo 9%; p = 0.023). Serious adverse events occurred in 10 patients receiving budesonide and 7 patients receiving placebo.

Conclusion: Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses.

Lay Summary: Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests. CLINICALTRIALS.

Gov Number: NCT00746486.
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http://dx.doi.org/10.1016/j.jhep.2020.09.011DOI Listing
February 2021

Diffusion-weighted magnetic resonance enterocolonography in assessing Crohn disease activity.

Pol Arch Intern Med 2020 09 6;130(9):734-740. Epub 2020 Jul 6.

Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania

Introduction: Diffusion‑weighted magnetic resonance imaging has the potential to identify inflamed bowel segments in patients with Crohn disease (CD).

Objectives: We aimed to determine diffusion‑weighted imaging (DWI) value to predict active CD and compare apparent diffusion coefficients (ADCs) with endoscopic and conventional indices of magnetic resonance imaging of CD activity.

Patients And Methods: Overall, 229 patients with suspected and diagnosed CD prospectively underwent magnetic resonance enterocolonography (MR‑EC) with DWI sequence and ileocolonoscopy. The magnetic resonance activity index (MaRIA), Clermont index, and CD endoscopic index of severity (CDEIS) were calculated.

Results: The clinical diagnosis of CD was confirmed in 100 out of 229 patients. A DWI score of 2 or higher had 96.9% sensitivity and 82.3% specificity for diagnosing CD. A threshold ADC value of 1.3 × 10-3 mm2/s could distinguish between normal and inflamed bowel segments with a sensitivity of 73.8% and a specificity of 98%. For the MaRIA, a threshold ADC value of 1.32 × 10-3 mm2/s with a sensitivity of 97.9% and a specificity of 97.8% was established. There were significant differences in the DWI scores and ADC values comparing patients with inactive, mild, and moderate-to-severe disease (P <0.01). ADCs inversely correlated with the MaRIAglobal (r = -0.69; P = 0.001), Clermontglobal (r = -0.722; P = 0.001), and CDEIS (r = -0.69; P = 0.001).

Conclusions: DWI is a valuable tool that is capable of identifying inflamed bowel segments as accurately as the conventional MaRIA score and of discriminating between mild and moderate-to-severe CD.
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http://dx.doi.org/10.20452/pamw.15487DOI Listing
September 2020

Gastritis Stages in Monozygotic and Dizygotic Dyspeptic Twins.

Gastroenterol Res Pract 2020 2;2020:9510717. Epub 2020 Jul 2.

Department of Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas LT-50161, Lithuania.

Background: The progression of -associated gastritis towards atrophic gastritis is modulated by host-related and environmental factors. Studies that explore the possible involvement of host-related versus environmental factors in the development of gastritis phenotype induced by are highly needed.

Aims: Our study was aimed at investigating the phenotype of -associated gastritis in two cohorts of monozygotic and dizygotic twins, using the OLGA/OLGIM gastritis staging system.

Methods: Two cohorts of monozygotic (14 pairs) and dizygotic (15 pairs) dyspeptic twins prospectively underwent endoscopy with biopsy sampling based on Sydney protocol. status and OLGA/OLGIM stages were assessed and compared.

Results: The mean age of monozygotic and dizygotic twins was 40.4 and 38.6 years, respectively ( = 0.623). The overall prevalence of infection was 51.7%. Among the 14 monozygotic twin pairs, five pairs were -positive, four were -negative, and five were -discordant. Among the 15 dizygotic twin pairs, five pairs were -positive, five were -negative, and five were -discordant. Concordance for antrum atrophy in monozygotic twins was 78.6% (11/14 pairs) and in dizygotic twins 73.3% (11/15 pairs) ( = 0.742). Concordance for corpus atrophy in monozygotic versus dizygotic twins was 92.9% (13/14 pairs) and 86.7% (13/15 pairs), respectively ( = 0.584). Concordance for antrum intestinal metaplasia (IM) in monozygotic twins was 85.7% (12/14 pairs) and in dizygotic 73.3% (11/15 pairs) ( = 0.411). Concordance for corpus IM in monozygotic twins was 85.7% (12/14 pairs) and in dizygotic 86.7% (13/15 pairs) ( = 0.941). Among monozygotic and dizygotic subjects, the stage of gastritis was concordant in both -positive and -negative subjects.

Conclusions: In conclusion, histological gastric mucosa alterations in monozygotic and dizygotic twins showed high rates of concordance. Furthermore, OLGA/OLGIM gastritis stages were not modulated by the zygosity of the twins.
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http://dx.doi.org/10.1155/2020/9510717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352144PMC
July 2020

Transient and Persistent Gastric Microbiome: Adherence of Bacteria in Gastric Cancer and Dyspeptic Patient Biopsies after Washing.

J Clin Med 2020 Jun 16;9(6). Epub 2020 Jun 16.

Department of Clinical Microbiology, Rigshospitalet, Henrik Harpestrengs Vej 4A, 2100 Copenhagen, Denmark.

is a common colonizer of the human stomach, and long-term colonization has been related to development of atrophic gastritis, peptic ulcers and gastric cancer. The increased gastric pH caused by colonization, treatment with antibiotics or proton pump inhibitors (PPI) may allow growth of other bacteria. Previous studies have detected non- bacteria in stomach biopsies, but no conclusion has been made of whether these represent a transient contamination or a persistent microbiota. The aim of this study was to evaluate the transient and persistent bacterial communities of gastric biopsies. The washed or unwashed gastric biopsies were investigated by cultivation and microbiota analysis (16S rRNA gene-targeted amplicon sequencing) for the distribution of and other non- bacteria. The number of cultured non- bacteria decreased in the washed biopsies, suggesting that they might be a transient contamination. No significant differences in the bacterial diversity were observed in the microbiome analysis between unwashed and washed biopsies. However, the bacterial diversity in biopsies shown -positive and -negative were significantly different, implying that is the major modulator of the gastric microbiome. Further large-scale studies are required to investigate the transient and persistent gastric microbiota.
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http://dx.doi.org/10.3390/jcm9061882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357088PMC
June 2020

Helicobacter pylori first-line and rescue treatments in patients allergic to penicillin: Experience from the European Registry on H pylori management (Hp-EuReg).

Helicobacter 2020 Jun 16;25(3):e12686. Epub 2020 Mar 16.

Department of Gastroenterology, Rabin Medical Center, Tel Aviv University, Petach Tikva, Israel.

Background: Experience in Helicobacter pylori eradication treatment of patients allergic to penicillin is very scarce. A triple combination with a PPI, clarithromycin (C), and metronidazole (M) is often prescribed as the first option, although more recently the use of a quadruple therapy with PPI, bismuth (B), tetracycline (T), and M has been recommended.

Aim: To evaluate the efficacy and safety of first-line and rescue treatments in patients allergic to penicillin in the "European Registry of H pylori management" (Hp-EuReg).

Methods: A systematic prospective registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H pylori infection. An e-CRF was created on AEG-REDCap. Patients with penicillin allergy were analyzed until June 2019.

Results: One-thousand eighty-four patients allergic to penicillin were analyzed. The most frequently prescribed first-line treatments were as follows: PPI + C + M (n = 285) and PPI + B + T + M (classic or Pylera ; n = 250). In first line, the efficacy of PPI + C + M was 69%, while PPI + B + T + M reached 91% (P < .001). In second line, after the failure of PPI + C + M, two rescue options showed similar efficacy: PPI + B + T + M (78%) and PPI + C + levofloxacin (L) (71%) (P > .05). In third line, after the failure of PPI + C + M and PPI + C + L, PPI + B + T + M was successful in 75% of cases.

Conclusion: In patients allergic to penicillin, a triple combination with PPI + C + M should not be generally recommended as a first-line treatment, while a quadruple regimen with PPI + B + T + M seems to be a better option. As a rescue treatment, this quadruple regimen (if not previously prescribed) or a triple regimen with PPI + C + L could be used but achieved suboptimal (<80%) results.
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http://dx.doi.org/10.1111/hel.12686DOI Listing
June 2020

How close are we to hepatitis C virus elimination in Central Europe?

Clin Exp Hepatol 2020 Feb 17;6(1):1-8. Epub 2020 Feb 17.

Department of Infectious Diseases, Jan Kochanowski University, Kielce, Poland.

Aim Of The Study: To collect and analyse data obtained from HCV opinion leaders/experts from central European countries, on factors which can affect the WHO target of HCV elimination by 2030.

Material And Methods: Data were collected from opinion leaders/experts involved in management of HCV infections in Central European countries which participated in 9 Conference of the Central European Hepatologic Collaboration (Warsaw, 10-11 October 2019). A dedicated questionnaire collected current information related to HCV elimination in Bulgaria, Croatia, the Czech Republic, Hungary, Latvia, Lithuania, Poland and Slovakia.

Results: The HCV prevalence rate in particular countries varied from 0.2% to 1.7%. In most central European countries all the HCV infected population is eligible for reimbursement of treatment. However, in some countries there are still some limitations related to the stage of the disease and people who inject drugs. All countries have access to at least one pangenotypic regimen. The most common barrier to HCV elimination in all countries is insufficient political will to establish priority for HCV. None of the reporting countries has established a national screening programme.

Conclusions: Access to therapy for HCV is similar and the majority of patients in Central Europe can be treated according to the current guidelines. Unfortunately there are still some limitations and a lack of political will to implement national screening programmes. According to collected data HCV elimination will not be possible in the region by 2030.
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http://dx.doi.org/10.5114/ceh.2020.93049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062123PMC
February 2020

Common variation in FAM155A is associated with diverticulitis but not diverticulosis.

Sci Rep 2020 02 3;10(1):1658. Epub 2020 Feb 3.

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.

Colonic diverticulosis is a very common condition. Many patients develop diverticulitis or other complications of diverticular disease. Recent genome-wide association studies (GWAS) consistently identified three major genetic susceptibility factors for both conditions, but did not discriminate diverticulititis and diverticulosis in particular due the limitations of registry-based approaches. Here, we aimed to confirm the role of the identified variants for diverticulosis and diverticulitis, respectively, within a well-phenotyped cohort of patients who underwent colonoscopy. Risk variants rs4662344 in Rho GTPase-activating protein 15 (ARHGAP15), rs7609897 in collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) and rs67153654 in family with sequence similarity 155 A (FAM155A) were genotyped in 1,332 patients. Diverticulosis was assessed by colonoscopy, and diverticulitis by imaging, clinical symptoms and inflammatory markers. Risk of diverticulosis and diverticulitis was analyzed in regression models adjusted for cofactors. Overall, the variant in FAM155A was associated with diverticulitis, but not diverticulosis, when controlling for age, BMI, alcohol consumption, and smoking status (OR 0.49 [95% CI 0.27-0.89], p = 0.002). Our results contribute to the assessment specific genetic variants identified in GWAS in the predisposition to the development of diverticulitis in patients with diverticulosis.
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http://dx.doi.org/10.1038/s41598-020-58437-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997170PMC
February 2020

Lemann Index for Assessment of Crohn's Disease: Correlation with the Quality of Life, Endoscopic Disease Activity, Magnetic Resonance Index of Activity and C- Reactive Protein.

Open Med (Wars) 2019 7;14:785-791. Epub 2019 Nov 7.

Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Aim: Crohn's disease (CD) is characterized by continuing inflammation and progressive gut damage. Despite many scoring indices of CD, there is a lack of more global assessment tools for the evaluation of the total disease impact on the gut.

Methods: Fift y-three adult patients with proven CD underwent magnetic resonance enterocolonography (MR-EC), colonoscopy, and clinical activity assessment, including CRP. Quality of life was assessed using IBDQ. MR-EC was used to evaluate the Magnetic Resonance Index of Activity (MaRIA- global (G)) and the Lemann Index (LI). The CD Endoscopic Index of Severity (CDEIS) was used to score the endoscopic activity of the disease.

Results: A signifi cant correlation between the LI and IBDQ was found (r=-0.812, P<0.01). LI and MaRIA-G correlated moderately, while the LI did not correlate significantly with CRP and CDEIS. For the detection of endoscopically active CD, MaRIA-G was more sensitive and specific (83.3%; 73.3%) compared to the LI (66.7%; 60.0%). There was a moderate correlation between CRP and MaRIA-G, as well as CRP and CDEIS (r=0.496; r=0.527,<0.01).

Conclusion: A signifi cant negative correlation between the LI and quality of life, measured by IBDQ, was found in our study, suggesting that the LI could resemble more global features of the disease, besides inflammatory activity of the gut.
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http://dx.doi.org/10.1515/med-2019-0092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843552PMC
November 2019

Mathematical morphology-based imaging of gastrointestinal cancer cell motility and 5-aminolevulinic acid-induced fluorescence.

Biomed Tech (Berl) 2019 Dec;64(6):711-720

Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, LT-44307, Lithuania.

The aim of this study was the quantitative evaluation of gastrointestinal cancer cell motility and 5-aminolevulinic acid (5-ALA)-induced fluorescence in vitro using mathematical morphology and structural analysis methods. The results of our study showed that MKN28 cells derived from the lymph node have the highest motility compared with AGS or HCT116 cells derived from primary tumors. Regions of single cells were characterized as most moving, and "tightly packed" cell colonies as nearly immobile. We determined the reduction of cell motility in late passage compared to early passage. Application of 5-ALA caused fluorescence in all investigated cells, and the fluorescence was different with regard to the cell type and application time. We observed higher fluorescence in MKN28 cells. Comprehensive image analysis did not reveal any statistically significant difference in fluorescence intensity between "tightly packed" cell regions, where nearly no motility was registered and loosely distributed cells, where the highest cell motility was registered. In conclusions, our study revealed that MKN28 cells derived from the lymph node have higher motility and 5-ALA-induced fluorescence than AGS or HCT116 derived from primary tumors. Moreover, image analysis based on a large amount of processed data is an important tool to study these tumor cell properties.
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http://dx.doi.org/10.1515/bmt-2018-0197DOI Listing
December 2019

Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis.

World J Gastroenterol 2019 Jun;25(23):2935-2946

Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania.

Background: Clinically significant portal hypertension (CSPH) and severe portal hypertension (SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor (PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce.

Aim: To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis, CSPH, SPH and potential to predict portal hypertension.

Methods: A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient (HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffness values were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age- and sex- matched individuals.

Results: Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis (23.20 9.85; < 0.0001 and 2.19 3.12; = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG ( = 0.338, = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG ( = -0.267, = 0.007). PlGF levels were higher in CSPH and SPH ( = 0.006; < 0.0001) whereas Nogo-A levels were lower ( = 0.01; < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68 ( = 0.003) and for Nogo-A - 0.67 ( = 0.01); for SPH 0.714 ( < 0.0001) and 0.65 ( = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices ( < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and 76.7% specificity; whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific (93.1%) for the diagnosis of CSPH.

Conclusion: Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.
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http://dx.doi.org/10.3748/wjg.v25.i23.2935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589742PMC
June 2019

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.

Lancet 2019 03 14;393(10174):899-909. Epub 2019 Feb 14.

Department of Obstetrics and Gynecology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv, Israel.

Background: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth.

Methods: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134.

Findings: We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001).

Interpretation: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 μmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery.

Funding: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust.
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http://dx.doi.org/10.1016/S0140-6736(18)31877-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396441PMC
March 2019

Efficacy of Per-oral Methylene Blue Formulation for Screening Colonoscopy.

Gastroenterology 2019 06 10;156(8):2198-2207.e1. Epub 2019 Feb 10.

Ospedale Nuovo Regina, Margherita, Gastroenterology Unit, Roma, Italy.

Background & Aims: Topically applied methylene blue dye chromoendoscopy is effective in improving detection of colorectal neoplasia. When combined with a pH- and time-dependent multimatrix structure, a per-oral methylene blue formulation (MB-MMX) can be delivered directly to the colorectal mucosa.

Methods: We performed a phase 3 study of 1205 patients scheduled for colorectal cancer screening or surveillance colonoscopies (50-75 years old) at 20 sites in Europe and the United States, from December 2013 through October 2016. Patients were randomly assigned to groups given 200 mg MB-MMX, placebo, or 100 mg MB-MMX (ratio of 2:2:1). The 100-mg MB-MMX group was included for masking purposes. MB-MMX and placebo tablets were administered with a 4-L polyethylene glycol-based bowel preparation. The patients then underwent colonoscopy by an experienced endoscopist with centralized double-reading. The primary endpoint was the proportion of patients with 1 adenoma or carcinoma (adenoma detection rate [ADR]). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for differences in detection between the 200-mg MB-MMX and placebo groups. False-positive (resection rate for non-neoplastic polyps) and adverse events were assessed as secondary endpoints.

Results: The ADR was higher for the MB-MMX group (273 of 485 patients, 56.29%) than the placebo group (229 of 479 patients, 47.81%) (OR 1.46; 95% CI 1.09-1.96). The proportion of patients with nonpolypoid lesions was higher in the MB-MMX group (213 of 485 patients, 43.92%) than the placebo group (168 of 479 patients, 35.07%) (OR 1.66; 95% CI 1.21-2.26). The proportion of patients with adenomas ≤5 mm was higher in the MB-MMX group (180 of 485 patients, 37.11%) than the placebo group (148 of 479 patients, 30.90%) (OR 1.36; 95% CI 1.01-1.83), but there was no difference between groups in detection of polypoid or larger lesions. The false-positive rate did not differ significantly between groups (83 [23.31%] of 356 patients with non-neoplastic lesions in the MB-MMX vs 97 [29.75%] of 326 patients with non-neoplastic lesions in the placebo group). Overall, 0.7% of patients had severe adverse events but there was no significant difference between groups.

Conclusions: In a phase 3 trial of patients undergoing screening or surveillance colonoscopies, we found MB-MMX led to an absolute 8.5% increase in ADR, compared with placebo, without increasing the removal of non-neoplastic lesions. Clinicaltrials.gov no: NCT01694966.
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http://dx.doi.org/10.1053/j.gastro.2019.02.001DOI Listing
June 2019

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

Gut 2019 05 19;68(5):854-865. Epub 2019 Jan 19.

University of Exeter Medical School, University of Exeter, United Kingdom, Exeter, UK.

Objective: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.

Design: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry.

Results: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near with a p value of 2.3×10 and 0.002 (OR=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, (OR 1.32, 95% CI 1.12 to 1.56), (OR 1.21, 95% CI 1.04 to 1.42), (OR 1.17, 95% CI 1.03 to 1.33) and (OR 1.17, 95% CI 1.03 to 1.33).

Conclusion: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
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http://dx.doi.org/10.1136/gutjnl-2018-317619DOI Listing
May 2019

Investigation of Radiofrequency Ultrasound-Based Fibrotic Tissue Strain Imaging Method Employing Endogenous Motion.

J Ultrasound Med 2019 Sep 4;38(9):2315-2327. Epub 2019 Jan 4.

Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Objectives: The paper presents the results of an initial clinical study, which were obtained using the strain elastography imaging method based on radio frequency ultrasound signal analysis.

Methods: The technique employs endogenous motion of the liver induced by beating heart and vascular pulsatility as an excitation source of tissue microdisplacement. The potential for fibrotic tissue characterization was demonstrated using a clinical data set of radio frequency ultrasound signals (23 healthy controls, 21 subjects with hepatitis, and 16 subjects with liver cirrhosis). Parametric maps, which represent the tissue strain, were derived from the gradient of the integrated spectral coefficient parameter, and correlations with the stage of liver disease were evaluated. Average endogenous strain derived from the gradient of the integrated spectral coefficient parameter and variability (standard deviation) of the strain were evaluated in the rectangular regions of interest (sizes, 1 × 1 and 2 × 2 cm) defined by the observer. The assessment of strain was performed in different frequency subbands of endogenous motion (0-10 Hz and 10-20 Hz).

Results: The best distinction between the groups was observed for the average strain derived from the gradient of the integrated spectral coefficient parameter: the controls, 13.30 ± 6.62; hepatitis, 7.12 ± 7.45; cirrhosis, 3.95 ± 2.44 μm/cm (region of interest, 1 × 1 cm; frequency subband 0-10 Hz), and 10.48 ± 6.02, 8.27 ± 5.41, 3.89 ± 2.07 μm/cm, respectively (2 × 2 cm, 0-10 Hz).

Conclusion: The investigated strain parameters showed statistically significant differences (P < .001) for the different stages of liver fibrosis in most of the cases and proved this method to be feasible.
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http://dx.doi.org/10.1002/jum.14925DOI Listing
September 2019

TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer.

J Gastrointestin Liver Dis 2018 Dec;27(4):363-369

Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Background And Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H. pylori infection, atrophic gastritis (AG) or GC in the European population.

Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum.

Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26-2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26-2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed.

Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.
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http://dx.doi.org/10.15403/jgld.2014.1121.274.tlrDOI Listing
December 2018

Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort: An Epi-IBD study.

J Gastroenterol Hepatol 2019 Jun 21;34(6):996-1003. Epub 2019 Jan 21.

Department of Gastroenterology, University Hospital of Ioannina, Ioannina, Greece.

Background And Aim: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) is not always possible, and a proportion of patients will be diagnosed as inflammatory bowel disease unclassified (IBDU). The aim of the study was to investigate the prognosis of patients initially diagnosed with IBDU and the disease course during the following 5 years.

Methods: The Epi-IBD study is a prospective population-based cohort of 1289 IBD patients diagnosed in centers across Europe. Clinical data were captured prospectively throughout the follow-up period.

Results: Overall, 476 (37%) patients were initially diagnosed with CD, 701 (54%) with UC, and 112 (9%) with IBDU. During follow-up, 28 (25%) IBDU patients were changed diagnoses to either UC (n = 20, 71%) or CD (n = 8, 29%) after a median of 6 months (interquartile range: 4-12), while 84 (7% of the total cohort) remained IBDU. A total of 17 (15%) IBDU patients were hospitalized for their IBD during follow-up, while 8 (7%) patients underwent surgery. Most surgeries (n = 6, 75%) were performed on patients whose diagnosis was later changed to UC; three of these colectomies led to a definitive diagnosis of UC. Most patients (n = 107, 96%) received 5-aminosalicylic acid, while 11 (10%) patients received biologicals, of whom five remained classified as IBDU.

Conclusions: In a population-based inception cohort, 7% of IBD patients were not given a definitive diagnosis of IBD after 5 years of follow-up. One in four patients with IBDU eventually was classified as CD or UC. Overall, the disease course and medication burden in IBDU patients were mild.
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http://dx.doi.org/10.1111/jgh.14563DOI Listing
June 2019

Identification of long intergenic non-coding RNAs (lincRNAs) deregulated in gastrointestinal stromal tumors (GISTs).

PLoS One 2018 17;13(12):e0209342. Epub 2018 Dec 17.

Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Long intergenic non-coding RNAs (lincRNAs) are >200 nucleotides long non-coding RNAs, which have been shown to be implicated in carcinogenic processes by interacting with cancer associated genes or other non-coding RNAs. However, their role in development of rare gastrointestinal stromal tumors (GISTs) is barely investigated. Therefore, the aim of this study was to define lincRNAs deregulated in GIST and find new GIST-lincRNA associations. Next-generation sequencing data of paired GIST and adjacent tissue samples from 15 patients were subjected to a web-based lincRNA analysis. Three deregulated lincRNAs (MALAT1, H19 and FENDRR; adjusted p-value < 0.05) were selected for expression validation in a larger group of patients (n = 22) by RT-qPCR method. However, only H19 and FENDRR showed significant upregulation in the validation cohort (adjusted p < 0.05). Further, we performed correlation analyses between expression levels of deregulated lincRNAs and GIST-associated oncogenes or GIST deregulated microRNAs. We found high positive correlations between expression of H19 and known GIST related oncogene ETV1, and between H19 and miR-455-3p. These findings expand the knowledge on lincRNAs deregulated in GIST and may be an important resource for the future studies investigating lincRNAs functionally relevant to GIST carcinogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209342PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296525PMC
May 2019

Natural Disease Course of Ulcerative Colitis During the First Five Years of Follow-up in a European Population-based Inception Cohort-An Epi-IBD Study.

J Crohns Colitis 2019 Feb;13(2):198-208

IBD Clinical and Research Centre, ISCARE, Prague, Czech Republic.

Background And Aims: Few population-based cohort studies have assessed the disease course of ulcerative colitis [UC] in the era of biological therapy and widespread use of immunomodulators. The aim of this study was to assess the 5-year outcome and disease course of patients with UC in the Epi-IBD cohort.

Methods: In a prospective, population-based inception cohort of unselected patients with UC, patients were followed up from the time of their diagnosis, which included the collection of their clinical data, demographics, disease activity, medical therapy, and rates of surgery, cancers, and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.

Results: A total of 717 patients were included in the study. During follow-up, 43 [6%] patients underwent a colectomy and 163 [23%] patients were hospitalised. Of patients with limited colitis [distal to the left flexure], 90 [21%] progressed to extensive colitis. In addition, 92 [27%] patients with extensive colitis experienced a regression in disease extent, which was associated with a reduced risk of hospitalisation (hazard ratio [HR]: 0.5 95% CI: 0.3-0.8]. Overall, patients were treated similarly in both geographical regions; 80 [11%] patients needed biological therapy and 210 [29%] patients received immunomodulators. Treatment with immunomodulators was found to reduce the risk of hospitalisation [HR: 0.5 95% CI: 0.3-0.8].

Conclusions: Although patients in this population-based cohort were treated more aggressively with immunomodulators and biological therapy than in cohorts from the previous two decades, their disease outcomes, including colectomy rates, were no different. However, treatment with immunomodulators was found to reduce the risk of hospitalisation.
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http://dx.doi.org/10.1093/ecco-jcc/jjy154DOI Listing
February 2019

Helicobacter pylori and nonmalignant upper gastrointestinal diseases.

Helicobacter 2018 Sep;23 Suppl 1:e12522

Institute of Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.

The review of the most important recent publications concerning the relation of Helicobacter pylori with peptic ulcer disease (PUD), noninvestigated and functional dyspepsia, and gastroesophageal reflux disease (GERD) is presented. H. pylori remains the main etiopathogenetic factor in complicated and uncomplicated PUD. Nevertheless, the role of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin is increasing. The novel data did not confirm that PUD caused by NSAIDs and aspirin is less symptomatic. The role of glucocorticoids, immunosuppressants, and antidepressants seems to be of some importance. Although the involvement of H. pylori in functional dyspepsia is controversial, several data support the importance of H. pylori-induced gastritis in the pathogenesis of dyspeptic symptoms. Recent interventional studies have reported that H. pylori eradication improves dyspepsia mainly in areas with a high prevalence of this bacterium. Novel data regarding the relation of gastrointestinal peptides, ghrelin and obestatin, with H. pylori infection are also presented. Intriguing findings support the involvement of the gastric microbiota in the causation of chronic functional dyspepsia. Finally, some data concerning negative, positive, or neutral associations of H. pylori with gastroesophageal reflux disease (GERD) were published. In this context, today there is no evidence indicating that H. pylori eradication could worsen the symptoms or the course of GERD.
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http://dx.doi.org/10.1111/hel.12522DOI Listing
September 2018

Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level.

Cancer Med 2018 10 6;7(10):5057-5065. Epub 2018 Sep 6.

Association of Medical Practices in Hematology and Internal Oncology, Troisdorf, Germany.

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10 ). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10 ). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.
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http://dx.doi.org/10.1002/cam4.1719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198243PMC
October 2018

Vitamin D deficiency in a European inflammatory bowel disease inception cohort: an Epi-IBD study.

Eur J Gastroenterol Hepatol 2018 11;30(11):1297-1303

Pekka Collin Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland.

Background: Serum vitamin D level is commonly low in patients with inflammatory bowel disease (IBD). Although there is a growing body of evidence that links low vitamin D level to certain aspects of IBD such as disease activity and quality of life, data on its prevalence and how it varies across disease phenotype, smoking status and treatment groups are still missing.

Materials And Methods: Patients diagnosed with IBD between 2010 and 2011 were recruited. Demographic data and serum vitamin D levels were collected. Variance of vitamin D level was then assessed across different treatment groups, disease phenotype, disease activity and quality of life scores.

Results: A total of 238 (55.9% male) patients were included. Overall, 79% of the patients had either insufficient or deficient levels of vitamin D at diagnosis. Patients needing corticosteroid treatment at 1 year had significantly lower vitamin D levels at diagnosis (median 36.0 nmol/l) (P=0.035). Harvey-Bradshaw Index (P=0.0001) and Simple Clinical Colitis Activity Index scores (P=0.0001) were significantly lower in patients with higher vitamin D level. Serum vitamin D level correlated significantly with SIBQ score (P=0.0001) and with multiple components of SF12. Smokers at diagnosis had the lowest vitamin D levels (vitamin D: 34 nmol/l; P=0.053).

Conclusion: This study demonstrates the high prevalence of low vitamin D levels in treatment-naive European IBD populations. Furthermore, it demonstrates the presence of low vitamin D levels in patients with IBD who smoke.
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http://dx.doi.org/10.1097/MEG.0000000000001238DOI Listing
November 2018

A Variant of COL3A1 (rs3134646) Is Associated With Risk of Developing Diverticulosis in White Men.

Dis Colon Rectum 2018 May;61(5):604-611

Department of Medicine II, Saarland University Medical Center, Homburg, Germany.

Background: Colonic diverticulosis is one of the most common gastroenterological disorders. Although diverticulosis is typically benign, many individuals develop diverticulitis or other aspects of diverticular disease. Diverticulosis is thought to stem from a complex interaction of environmental, dietary, and genetic factors; however, the contributing genetic factors remain unknown.

Objective: The aim of our present study was to determine the role of genetic variants within genes encoding for collagens of the connective tissue in diverticulosis.

Design: This was a transsectional genetic association study.

Settings: This study was conducted at three tertiary referral centers in Germany and Lithuania.

Patients: Single-nucleotide polymorphisms in COL3A1 (rs3134646, rs1800255) and COL1A1 (rs1800012) were genotyped in 422 patients with diverticulosis and 285 controls of white descent by using TaqMan assays.

Main Outcome Measures: The association of colonoscopy-proven diverticulosis with genetic polymorphisms with herniations was assessed in multivariate models.

Results: The rs3134646, rs1800255, and rs1800012 variants were significantly associated with the risk of developing diverticulosis in the univariate model; however, these associations were not significant in the multivariate logistic regression analysis including additional nongenetic variables. When selectively analyzing sexes, the genotype AA (AA) in rs3134646 remained significantly associated with diverticulosis in men (OR, 1.82; 95% CI, 1.04-3.20; p = 0.04).

Limitations: Because a candidate approach was used, additional relevant variants could be missed. Within our cohort of patients with diverticulosis, only a small proportion had diverticular disease and thus, we could not examine the variants in these subgroups. Functional studies, including the analysis of the involved collagens, are also warranted.

Conclusions: Our study shows that a variant of COL3A1 (rs3134646) is associated with the risk of developing colonic diverticulosis in white men, whereas rs1800255 (COL3A1) and rs1800012 (COL1A1) were not associated with this condition after adjusting for confounding factors. Our data provide novel valuable insights in the genetic susceptibility to diverticulosis. See Video Abstract at http://links.lww.com/DCR/A504.
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http://dx.doi.org/10.1097/DCR.0000000000001001DOI Listing
May 2018

Natural disease course of Crohn's disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.

Gut 2019 03 23;68(3):423-433. Epub 2018 Jan 23.

IBD Clinical and Research Centre, ISCARE, Prague, Czech Republic.

Objective: The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn's disease (CD).

Design: Patients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.

Results: In total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5).

Conclusion: Despite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.
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http://dx.doi.org/10.1136/gutjnl-2017-315568DOI Listing
March 2019

Noninvasive Evaluation of Portal Hypertension Using a Supervised Learning Technique.

J Healthc Eng 2017 12;2017:6183714. Epub 2017 Oct 12.

Biomedical Engineering Institute, Kaunas University of Technology, Kaunas, Lithuania.

Portal hypertension (PHT) is a key event in the evolution of different chronic liver diseases and leads to the morbidity and mortality of patients. The traditional reliable PHT evaluation method is a hepatic venous pressure gradient (HVPG) measurement, which is invasive and not always available or acceptable to patients. The HVPG measurement is relatively expensive and depends on the experience of the physician. There are many potential noninvasive methods to predict PHT, of which liver transient elastography is determined to be the most accurate; however, even transient elastography lacks the accuracy to be a perfect noninvasive diagnostic method of PHT. In this research, we are focusing on noninvasive PHT assessment methods that rely on selected best-supervised learning algorithms which use a wide set of noninvasively obtained data, including demographical, clinical, laboratory, instrumental, and transient elastography measurements. In order to build the best performing classification meta-algorithm, a set of 21 classification algorithms have been tested. The problem was expanded by selecting the best performing clinical attributes using algorithm-specific filtering methods that give the lowest error rate to predict clinically significant PHT. The suggested meta-algorithm objectively outperforms other methods found in literature and can be a good substitute for invasive PHT evaluation methods.
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http://dx.doi.org/10.1155/2017/6183714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660781PMC
July 2019

Primary antibiotic resistance of Helicobacter pylori strains among adults and children in a tertiary referral centre in Lithuania.

APMIS 2018 Jan 13;126(1):21-28. Epub 2017 Nov 13.

Department of Clinical Microbiology 9301, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

The study evaluated primary antibiotic resistance of Helicobacter pylori within the period 2013-2015 and trends of antibiotic consumption over the last decade in Lithuania; 242 adults and 55 children were included in the study. E-tests were performed for amoxicillin, metronidazole, clarithromycin, ciprofloxacin, rifampicin and tetracycline. The presence of H. pylori and clarithromycin resistance was additionally tested by PCR. Helicobacter pylori culture was positive in 67 of 242 (28%) adult and in 12 of 55 (21.8%) children samples. Resistance rates among adults by E-tests were as follows: metronidazole - 32.8% (95% confidence interval (CI): 22.7-44.7%), ciprofloxacin - 7.5% (95% CI: 3.2-16.3%), rifampicin - 7.5% (95% CI: 3.2-16.3%), amoxicillin - 0%, whereas resistance rates in children were as follows: metronidazole - 25% (95% CI: 8.9-53.2%), rifampicin - 8.3% (CI: 1.5-35.4%), amoxicillin and ciprofloxacin - 0%. Accumulated clarithromycin resistance rates by E-tests and PCR were 8.2% (95% CI: 4.1-16.0%) in adults and 17.7% (95% CI: 6.2-41.0%) in children. Total use of macrolides and lincosamides in Lithuania increased from 1.26 to 1.86 defined daily dose (DDD)/1000 inhabitants/day among adults, while it has doubled from 1.10 to 2.22 DDD/1000/children/day in children within 2003-2015. There are no significant changes in the susceptibility of H. pylori to the most widely used antibiotics in adults over the last years in Lithuania; however, clarithromycin resistance among children exceeds 15% and mandates further larger-scale studies in paediatric population.
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http://dx.doi.org/10.1111/apm.12752DOI Listing
January 2018

A comprehensive, cell specific microRNA catalogue of human peripheral blood.

Nucleic Acids Res 2017 Sep;45(16):9290-9301

Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.

With this study, we provide a comprehensive reference dataset of detailed miRNA expression profiles from seven types of human peripheral blood cells (NK cells, B lymphocytes, cytotoxic T lymphocytes, T helper cells, monocytes, neutrophils and erythrocytes), serum, exosomes and whole blood. The peripheral blood cells from buffy coats were typed and sorted using FACS/MACS. The overall dataset was generated from 450 small RNA libraries using high-throughput sequencing. By employing a comprehensive bioinformatics and statistical analysis, we show that 3' trimming modifications as well as composition of 3' added non-templated nucleotides are distributed in a lineage-specific manner-the closer the hematopoietic progenitors are, the higher their similarities in sequence variation of the 3' end. Furthermore, we define the blood cell-specific miRNA and isomiR expression patterns and identify novel cell type specific miRNA candidates. The study provides the most comprehensive contribution to date towards a complete miRNA catalogue of human peripheral blood, which can be used as a reference for future studies. The dataset has been deposited in GEO and also can be explored interactively following this link: http://134.245.63.235/ikmb-tools/bloodmiRs.
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http://dx.doi.org/10.1093/nar/gkx706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766192PMC
September 2017

The Prevalence of Cancer-Associated Autoantibodies in Patients with Gastric Cancer and Progressive Grades of Premalignant Lesions.

Cancer Epidemiol Biomarkers Prev 2017 10 2;26(10):1564-1574. Epub 2017 Aug 2.

Cancer Biomarker and Immunotherapy Group, Latvian Biomedical Research and Study Centre, Riga, Latvia.

Serum autoantibodies against tumor-associated antigens (TAAs) are detectable in early-stage gastric cancer patients; however, the time point during cancerogenesis when they appear in circulation is still obscure. In this study, we developed a recombinant antigen microarray and analyzed the prevalence of autoantibodies against 102 TAAs in 829 gastric cancer patients and 929 healthy controls from Caucasian and Asian populations, as well as 100 patients with chronic atrophic gastritis and 775 individuals staged according to different grades of intestinal metaplasia. Six antigens, including CTAG1B/CTAG2, DDX53, IGF2BP2, TP53, and MAGEA3, were predominantly reacting with sera from gastric cancer patients when compared with healthy controls, and the seroreactivity was associated with intestinal-type gastric cancer, but not with patients' status, grade, age, gender, or stage of gastric cancer. We detected gastric cancer-associated seroreactivity in 13% of patients with advanced/severe intestinal metaplasia, which was increased in comparison with mild/moderate intestinal metaplasia (5.3%) and was comparable with that seen in early-stage gastric cancer patients (12%). Moreover, by testing serum samples taken 1 to 9 years before the clinical diagnosis of 18 incident gastric cancer cases, we detected autoantibody responses against several TAAs-SOX2, MYC, BIRC5, IGF2BP1, and MUC1. Our results suggest that humoral immune response against TAAs is generated already during premalignant stages. Based on the obtained results, cancer-associated autoantibodies might make a valuable contribution to the stratification of high-risk patients with premalignant lesions in the stomach through enhancing the positive predictive power of existing risk models. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-0238DOI Listing
October 2017